Head and neck cancer (HNC) requires a multidisciplinary management, especially in locally advanced stage disease. Treatment advances in surgery, radiation therapy (RT) and chemotherapy are partially responsible for improvement in survival. Therefore a superior number of survivors run into acute and long-term consequences of HNC treatment. Physiologic functions preservation becomes paramount. Platinum-based chemotherapy with concomitant RT is the principal non surgical treatment, mainly with the aim of avoiding surgical destructive results. Although approximately 25% of HNC patients are aged 70 years and over, in the the past decades elderly patients were particularly under-represented in the clinical trials, accounting fewer than 10% of participants. Elderly population is highly heterogeneous, due to age-based differences in coexisting comorbidities, global performance status and geriatric syndromes such as cognitive and functional disabilities. Often treatments with curative intent are not offered to elderly, for fear of major side effects , reduced quality of life and death.
We designed a pilot study exclusively for elderly patients. The purpose is to analyze the clinical outcomes and the treatment tolerance of moderate hypofractionated RT with a total dose of 60 Gy in 20 fractions, 5 daily fractions/week, plus concomitant cetuximab, monoclonal antibody against the epidermal growth factor receptor (EGFR), in elderly patients with locally advanced HNC. Cetuximab will be administered at an initial loading dose of 400 mg/m2 one week before RT, followed by weekly injections at 250 mg/m2 during RT. The aim is to achieve a good rate of tumor control without toxicity increase, also thanks to Intensity Modulation Radiotherapy (IMRT) and image-guided RT (IGRT). It is hoped that this study will be potentially useful as a reference in the future for a multi-center randomized controlled clinical trial evaluating the best treatment approach in this setting of patients.
Nowadays definitive RT represents the standard of care in HNC treatment. The meta-analysis of chemotherapy in head and neck cancer (MACH-NC) defined an 8% survival benefit in adding chemotherapy concomitantly to RT [1]. The magnitude of the benefit of concomitant chemotherapy was significantly less in older patients. In addition, it should be noticed that concurrent chemoradiotherapy is associated with high rates of severe and protracted acute toxicities, especially mucositis, and more late adverse events like swallowing dysfunction and the need for nutritional support. Currently, in elderly population, the optimal treatment regimen is still an unresolved issue
Elderly patients may be particularly prone to such adverse events, due to reduced performance status or coexisting conditions. Therefore the generally greater toxicity of concomitant treatment places limits on the incremental improvements in efficacy gained by the addition of chemotherapy. Quality of life plays a progressively more important role in the evaluation of overall treatment efficacy. Due to decreasing effect and increasing toxicity of chemotherapy with age, RT alone should be proposed in this setting of patients. Standard target volumes delineation, with inclusion of negative nodal at risk, and standard total dose prescription, with conventional fractionation, are generally chosen. RT-related toxicity depends mostly on the total dose delivered to the normal tissues adjacent to the target volume and also on the volume of treatment. In order to obtain an acceptable toxicity, reduce total treatment duration time to ensure better compliance and assure treatment efficacy, we propose a definitive hypofractionated RT localized only to the macroscopic tumor volume plus concurrent cetuximab administration.
On the other hand, cetuximab improves the effect of RT, in term of loco-regional control and mortality without exacerbate the common RT-related toxicity [2]. Cetuximab is IgG1 monoclonal antibody against the epidermal growth factor receptor (EGFR), which is abnormally activated in HNC. It has been proved, in a randomized trial, to be superior to RT alone and represents a valid therapeutic option in HNC scenario.
Hypofractionated radiotherapy (HFRT) is defined as a treatment with single dose > 2.5 Gy: the aim is to achieve improved tumor control at expense of a moderate toxicity increase. In recent years the use of IMRT has allowed a steep dose gradient around the tumor with high dose conformity and image-guided RT (IGRT) has improved certainty regarding daily treatment setup and dose delivered to organs at risk. Recently a growing body of literature has indicated the safety and feasibility of HFRT for tumors of HNC .Controversies do exist regarding the appropriateness of the linear-quadratic model in the setting of high-single dose and total dose of radiotherapy. LQ models seem better fit the observed cell kill in vitro from higher doses per fraction. We then use the LQ model and EQD-2 Gy to compare the hypofractionated doses used in our study and a "biologically equivalent" fractionated course at 2 Gy single fraction.in The chosen dose of 60 Gy in 20 fractions, assuming an alfa/beta ratio of 10 for tumor, is equivalent to 65 Gy in 33 fractions for tumor and, with a median alfa/beta ratio of 3 for organ at risk, is equivalent to 72 Gy for normal tissues: smaller fields used than the current standard should reduce the effects on healthy organs at risk . We believe that this choice is a good compromise between a good locoregional control and an acceptable toxicity to healthy organs. Furthermore hypofractionated treatment limited only to cancer evidenced by sophisticated diagnostic investigations such as DW-MRI should optimize patient and caregiver convenience and should be related with lower acute toxicity: indeed the reduction of fraction numbers allows for better life quality in elderly patients by reducing the time spent in hospital.
Our combined approach could have a pronounced effect on loco-regional control, compared to RT alone, suggesting that RT and cetuximab may be complementary in elderly HNC patients. However, in elderly HNC patients, the role of cetuximab, as well as the risks of concomitant treatment, remains to be determined. Thus, it will be also important to evaluate whether cetuximab adversely affects the compliance to RT, which remains the most important component of this concomitant strategy.
1.Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4-14.
2. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-78.